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Keywords:

  • melanoma;
  • BRAF inhibitor;
  • brain metastases;
  • dabrafenib;
  • response;
  • progression

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURE
  9. REFERENCES

BACKGROUND

Dabrafenib has activity in patients with brain metastases, but little is known of the relative efficacy of treatment within and outside the brain. This study sought to examine the intracranial (IC) and extracranial (EC) patterns of response and progression in patients with active melanoma brain metastases treated with dabrafenib.

METHODS

Clinicopathologic parameters were collected on patients with active brain metastases enrolled in the phase 1 and 2 studies of dabrafenib at a single institution. RECIST (Response Evaluation Criteria In Solid Tumors) response and progression-free survival (PFS) were prospectively assessed by disease site (IC versus EC). Treatments received after disease progression were also assessed.

RESULTS

A total of 23 patients were studied. Response rates were similar in IC (78%) and EC (90%) sites (P = .416). IC and EC response was concordant in 71% of patients. Median site-specific PFS was identical in both IC and EC sites (23.6 weeks, P = .465), and exceeded whole-body PFS determined by RECIST (16.3 weeks). Of 20 patients with progressive disease (PD), 6 had IC PD only, 6 had EC PD only, and 8 had PD in both sites. In those with isolated intracranial PD, 5 of 6 underwent local therapy to the brain and continued on dabrafenib longer than 30 days.

CONCLUSIONS

IC and EC melanoma metastases respond similarly to dabrafenib. There is no dominant site or pattern of disease progression in patients with brain metastases treated with dabrafenib. Salvage local therapy is possible in most patients after IC disease progression, with ongoing dabrafenib treatment possible in a subset of patients. Cancer 2014;120:530–536. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURE
  9. REFERENCES

Melanoma commonly metastasizes to the brain. Twenty percent of patients have brain metastases at diagnosis of stage IV disease,[1] and approximately 50% ultimately develop them through the course of disease.[2] They occur more frequently in those with BRAF -mutant than BRAF wild-type melanoma.[1] Brain metastases carry a poor prognosis, with a median survival of 3 to 5 months from diagnosis, contributing to death in up to 50% of patients.[2, 3] Surgery and radiotherapy can provide local control and improvement in neurological symptoms in those with limited disease,[4] but until the availability of selective BRAF inhibitors, systemic therapies had limited efficacy, with response rates of no more than 10%.[2, 4-8]

BRAF inhibitors have significant activity in patients with melanoma brain metastases, as seen in the phase 1 and 2 clinical trials of dabrafenib[9, 10] and the pilot study of vemurafenib.[11] The phase 2 trial of dabrafenib in 172 patients with progressing brain metastases with or without prior local treatment demonstrated an intracranial (IC) response rate of 30% to 40%, an IC disease control rate of > 80%, a median progression-free survival (PFS) of 16.1 and 16.6 weeks in 2 cohorts, and a median overall survival (OS) of 33.1 and 31.4 weeks in the same cohorts of BRAFV600E (Val600Glu substitution in BRAF) metastatic melanoma patients. Although this study demonstrated unprecedented efficacy in patients with both untreated and previously treated brain metastases, it did not report data regarding the extracranial (EC) response to therapy in patients on the trial, nor did it examine the degree of concordance of response to therapy within individual patients (IC versus EC). No studies to date have examined the nature of disease progression in patients with brain metastases treated with BRAF inhibitors, nor have they examined treatments received afterward.

There are now several strategies for the management of brain metastases in patients with metastatic melanoma, including surgery, radiotherapy, immunotherapy, and BRAF inhibitors. In order to assist with the translation of clinical trial data into effective patient care, particularly for patients with IC and EC disease at the time of first diagnosis of metastatic disease, it is critical to understand the comparative IC and EC tumor response to BRAF inhibition, the nature of disease progression, and the effective management of patients after intracranial disease progression. In this study, we sought to analyze the nature of IC and EC response and progression in patients with melanoma brain metastases treated with dabrafenib, and hypothesized that IC and EC metastases respond and progress similarly to BRAF inhibitors.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURE
  9. REFERENCES

Patient Selection

The study was undertaken at Westmead Hospital in association with the Melanoma Institute of Australia (NSW, Australia), with Human Research Ethics Committee approval and patient informed consent. All patients who were enrolled in the brain cohort of the phase 1 trial[9] and the phase 2 brain metastasis trial (BREAK-MB)[10] of dabrafenib at Westmead Hospital between September 2009 and June 2011 were assessed. Patients were eligible for enrollment if they had BRAFV600E or BRAFV600K metastatic melanoma as assessed by high-resolution melt analysis and sequencing (phase 1 trial), or trial-specific polymerase chain reaction–based test (phase 2 trial), and either: 1) untreated, or 2) progressive but previously locally treated asymptomatic brain metastases (progression in the brain was determined using RECIST [Response Evaluation Criteria In Solid Tumors] version 1.0 for the phase 1 trial or modified RECIST version 1.1 in the phase 2 trial).[12, 13] Previous local brain treatment included surgery, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or a combination of local therapies. At least 1 measurable IC lesion (≥ 0.3 cm and ≤ 4 cm for the phase 1 trial, ≥ 0.5 cm and ≤ 4 cm for the phase 2 trial) as determined by gadolinium-enhanced magnetic resolution imaging (MRI) was required for trial entry. Concomitant corticosteroids were permitted if at a stable or reducing dose, and prophylactic or preventative antiepileptic therapy was allowed. Patients were allowed up to 2 lines of prior systemic treatment excluding mitogen-activated protein kinase inhibitors and were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

BRAF Inhibitor Treatment

All patients were treated with dabrafenib at the recommended phase 2 dose (RP2D) of 150 mg twice daily (bid), except for one patient on the phase 1 trial who commenced 70 mg bid and was escalated to the RP2D after 12 weeks. Patients with progressive disease (PD), defined as either IC, EC, or overall (as per RECIST criteria), were allowed to continue on dabrafenib if deemed to have ongoing clinical benefit from this treatment, including after local therapies (surgery, radiotherapy).

Disease Assessments

Baseline demographics including patient age, sex, BRAF genotype, the date of diagnosis of stage IV disease, and diagnosis of first brain metastasis, as well as details of prior brain metastasis treatment were collected. Baseline clinicopathologic parameters examining the patient's burden of disease including lactate dehydrogenase level and RECIST sum of diameters (SoD) of target lesions (IC, EC, and overall total [SoD of IC and EC]). In addition, computed tomography (CT) and MRI scans were reviewed, and the sites of EC metastases as well as the total number of IC and EC metastases were collected. The number and site of EC metastases were recorded, and patients with ≥20 IC metastases were classified into groups (20-30, 30-40, 40-50 metastases).

Disease assessments performed during treatment included clinical assessment every 4 weeks and imaging studies (cerebral MRI and chest, abdomen, and pelvis CT scans) at week 4, week 8, and every 8 weeks thereafter. RECIST criteria (version 1.0 for the phase 1 trial, version 1.1 for the phase 2 trial)[12, 13] were used to determine disease response extracranially, and modified RECIST[10] was used to assess intracranial response. Overall response was determined by combining the RECIST SoD of target lesions at both IC and EC sites.[10] Concordance of IC and EC response was defined as either partial/complete response (PR/CR, IC, and EC), stable disease (SD, IC, and EC), or progressive disease (PD, IC, and EC). We determined disease progression at IC and EC sites separately based on RECIST criteria. For PFS, we used the earliest progressing site (IC or EC) and not the overall RECIST SoD, which was used in determining progression in BREAK-MB.[10]

Statistical Methods

All statistical analyses were carried out with IBM SPSS Statistic, version 19.0. Univariate survival analyses were conducted with the Kaplan-Meier method together with the log-rank (Mantel-Cox) test for statistical significance of categorical variables. Cox regression was used to test survival for continuous variables. P values < .05 were considered statistically significant. PFS was defined as the time interval in days from commencement of dabrafenib to the first date of progression intracranially (IC PFS), extracranially (EC PFS), or overall (overall PFS, defined as PFS of the first progressing site). In those with PD in either IC or EC sites alone who continued on dabrafenib treatment beyond progression for ongoing clinical benefit, PFS for the other site was calculated. OS was defined as the time interval in days from commencement of dabrafenib to the date of last follow-up or death. All patient deaths in this cohort were attributed to melanoma.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURE
  9. REFERENCES

Patient Characteristics

Twenty-three patients were included for analysis, and baseline characteristics are shown in Table 1. Twelve patients (52%) had no prior local treatment for brain metastases, and 11 patients (48%) had received prior local treatment with subsequent disease progression intracranially. These groups were not analyzed separately due to the small patient numbers and unbalanced baseline characteristics. Patients had a median of 4 IC and 10 EC metastases, with a median RECIST SoD of 17 mm (IC) and 85 mm (EC) at baseline. One patient had no EC disease at trial entry, and another had EC disease that was not RECIST-measurable, and neither were included for EC response assessment. The median number of EC sites was 4 with a range of 1 to 8 sites, reflecting variable burden of EC disease.

Table 1. Baseline Patient and Disease Characteristics
CharacteristicTotal N (%)
  1. Abbreviations: BM, brain metastases; EC, extracranial; ECOG, Eastern Cooperative Oncology Group performance status; IC, intracranial; LDH, lactate dehydrogenase; SoD, sum of diameter; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; ULN, upper limit of normal.

Sex 
Male15 (65%)
Female8 (35%)
Age at trial start (years) 
Median (range)58 (23-82)
BRAF genotype 
V600E19 (83%)
V600K4 (17%)
BM at stage IV diagnosis 
Yes10 (43%)
No13 (57%)
Previous local treatment to BM 
Nil12 (52%)
Surgery3 (13%)
SRS1 (4%)
WBRT2 (9%)
Combination5 (22%)
Baseline ECOG 
ECOG 013 (57%)
ECOG 110 (43%)
Baseline LDH 
≤ULN9 (39%)
>ULN14 (61%)
Total number of IC metastases 
Median (range)4 (1-50)
RECIST SoD of IC targets (mm) 
Median (range)17 (4-91)
Total number of EC metastases 
Median (range)4 (0-50)
RECIST SoD of EC targets (mm) 
Median (range)85 (0-226)
Number of EC sites 
Median (range)4 (1-8)
Clinical trial 
Phase 16
Phase 217
Total23

Response, PFS, and OS

The overall, IC, and EC response rates, and PFS as well as OS, are shown in Table 2. The overall response rate was 87% (20 of 23 patients), with median time to best response of 7.7 weeks, median PFS of 16.3 weeks, and median OS of 36.6 weeks. IC and EC response rates were similar at 78% (18 of 23 patients) and 90% (19 of 21 patients), respectively (P = .416). There was a trend toward shorter time to best response in the IC compared with EC sites (median 7.4 versus 12.4 weeks, P = .107). The median PFS was similar in IC and EC sites (23.6 weeks each, P = .465).

Table 2. Response, Progression-Free Survival, and Overall Survival Based on Site of Disease
 OverallIntracranialExtracranialaPb
  1. Abbreviations: CI, confidence interval; PD/SD, progressive/stable disease; PR/CR, partial/complete response; RECIST, Response Evaluation Criteria In Solid Tumors.

  2. a

    One patient did not have measurable extracranial disease, one patient did not have extracranial disease. Neither included in extracranial response assessment.

  3. b

    Comparing intracranial versus extracranial disease.

  4. c

    Comparing PD/SD versus PR/CR, Fisher's exact test.

RECIST response category    
Progressive disease1100.416c
Stable disease242
Partial response201619
Complete response020
Total232321 
Time to best response    
Total N232321 
Median (weeks) (95% CI)7.7 (6.4-9.1)7.4 (7.0-7.9)12.4 (8.4-16.5)0.107
Range (weeks)3.4-31.33.4-31.33.4-24.3
Progression-free survival    
N progressed201816 
Median (weeks) (95% CI)16.3 (14.1-18.5)23.6 (13.6-33.6)23.6 (13.9-33.2)0.465
Range (weeks)4.0-44.94.0-58.94.0-56.9
Overall Survival    
N died17   
Median (weeks) (95% CI)36.6 (22.2-50.9)---
Range14.4-103.1   

Intrapatient IC and EC Concordance of Response

For those with measurable IC and EC disease at baseline as per RECIST (N = 21), IC and EC best RECIST response category was concordant (ie, PR/CR IC and EC; SD IC and EC; or PD IC and EC) in 15 (71%) patients. The degree of response was also similarly concordant (Fig. 1). Only one patient had tumor growth in EC disease (although still classified as stable disease) with shrinkage in IC disease.

image

Figure 1. Scatter plot demonstrates concordance of best response (percent change in sum of diameters of target lesions from baseline) in intracranial (IC) and extracranial (EC) sites within each patient (N = 21).

Download figure to PowerPoint

Disease Progression

Twenty patients had PD at the time of analysis: 30% (N = 6) of patients progressed in IC sites alone, 40% (N = 8) progressed in both IC and EC sites simultaneously, whereas 30% (N = 6) progressed in EC sites alone with ongoing IC response (Table 3). There was no dominant pattern to the nature of progression (new versus existing lesions, IC versus EC site); however, no patients progressed due to the development of new lesions alone.

Table 3. Site and Time to First Progression for Each Patient From Commencement of Treatment, Arranged According to Site of Progression
Pt.Rx to BM Prior to Trial EntryIC SoD at Baseline (mm)Best % Response in IC LesionsProgressionLocal Rx to IC Lesions Post-IC PDDabrafenib Rx Post-PD (days)Survival After First PD (days)OS From Start of Study (days)
Site of First PDNew IC metExisting IC metNew EC metExisting EC metTTFP
  1. a

    Ongoing at data cut;

  2. b

    patient alive at last follow-up;

  3. c

    duration of follow-up;

  4. d

    duration on treatment.

  5. Abbreviations: BM, brain metastasis; EC, extracranial; IC, intracranial; met, metastasis; N/A, not applicable; OS, overall survival; PD, progressive disease; Pt., patient; Rx, treatment; SoD, sum of diameter; SRS, stereotactic radiosurgery; Sx, surgery; TTFP, time to first progression; WBRT, whole-brain radiotherapy; X, site of progression; #, no IC progression.

1nil42−57ICXX  110WBRT6688198
2Sx, WBRT61−5ICXX  95Nil010105
3SRS100ICXX  108Sx89a89a197b
4nil42−64ICXX  127WBRT147184311
5nil6−67IC X  209Sx273513a722b
6Sx30−53IC X  314SRS8a8a323b
7nil13−46IC & ECXX X28WBRT1685113
8Sx, WBRT91−41IC & ECXX X84Nil117101
9nil80IC & ECX  X100WBRT3156256
10WBRT91−43IC & EC XX 220SRS7070290
11WBRT44−11IC & EC XXX52Nil3255107
12nil6−50IC & EC XXX165nil5583a248b
13nil36−39IC & EC X X114WBRT342156
14Sx, SRS31−42IC & EC X X112Nil2842154
15nil4−100EC  XX155#0151306
16>nil10−70EC   X220#7188308
17Sx, WBRT, SRS28−25EC   X112#204208320
18Sx9−67EC   X113#53102215
19Sx, WBRT11−55EC   X109#2273182
20nil6−100EC   X294#86148230
21nil17 No PD    294c N/AN/A294b
22Sx8 No PD    211c N/AN/A211b
23nil20 Ceased Rx prior to PD    80d N/AN/A224

Management After Disease Progression

In those with isolated IC progression (N = 6) (Table 3), 5 underwent local therapy to the brain. Two patients underwent SRS, 2 patients underwent surgery, and one patient received WBRT. The patient who did not receive subsequent treatment to the brain had received prior local brain treatment prior to trial entry (surgery and WBRT) and the lesions were not amenable to further therapy. Five of the 6 patients continued on dabrafenib for > 30 days after progression, with one patient continuing on treatment for 39 weeks after surgery to an isolated progressing IC lesion. In those who progressed at both IC and EC sites (N = 8) (Table 3), 4 received salvage local therapy to IC metastases and 3 patients continued on dabrafenib (> 30 days) after progression. In patients with isolated EC progression (N = 6), 4 continued on dabrafenib (> 30 days) after progression.

In total, 14 patients had IC progression (isolated or in combination with EC progression). Five patients underwent SRS/surgery, another 5 patients underwent WBRT, and further treatment of the progressing lesion(s) was not possible in the remaining 4 patients. In the SRS/surgery group, the median duration of dabrafenib continuation beyond progression was 11 weeks (range, 5-39 weeks) (Table 3).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURE
  9. REFERENCES

Several trials have demonstrated BRAF inhibitors are active in patients with melanoma brain metastases.[9-11] To the authors' knowledge, this is the first study to assess the nature of IC and EC response and progression in patients with melanoma brain metastases treated with a BRAF inhibitor. Results from this study of dabrafenib treatment suggest that IC and EC melanoma metastases respond in a concordant manner, with high response rates and similar PFS. Disease progression in those with brain metastases treated with dabrafenib is heterogeneous, and the brain is not necessarily the site of treatment failure in patients with active brain metastases at start of treatment. The results of this study are strengthened by the inclusion of patients with a broad spectrum of IC and EC disease burden, the detailed assessment of both IC and EC disease during treatment, and the inclusion of multiple clinicopathologic parameters for analysis.

The median PFS and OS seen in this study (16 and 36 weeks, respectively) are similar to those reported in the BREAK-MB trial[10] (16 and 32 weeks, respectively), suggesting that the patients included in this study are a representative subgroup of the phase 2 trial. The response rates in both IC and EC sites observed in this study are higher than those previously reported in trials,[9, 10, 14, 15] potentially due to the bias introduced by the single radiologist reporting every scan. This bias affected assessment of both IC and EC sites in equal measure, however, and therefore should not have significantly influenced comparative response assessments.

Our data show that disease control in the brain is similar to that in EC sites, and the IC and EC “site-specific” PFS was the same (median, 23 weeks). “Whole body” PFS, however, was shorter (median, 16 weeks). The explanation for this is that site-specific PFS only measures a subset of the total disease. Almost a third of patients progressed in EC sites with ongoing IC disease control. Overall, this is an important illustration of the fact that formal “whole body” RECIST reporting of studies of patients with brain metastases may underrepresent the rate of disease control in the brain. This could also explain the shorter PFS in BREAK-MB (median, 16 weeks) compared to that reported for studies of dabrafenib in patients with exclusively EC disease (5-6 months).[9, 14, 15]

After IC disease progression, local treatment to progressing lesions with concurrent ongoing dabrafenib treatment was used in several patients. This “salvage” local treatment enabled many patients to remain on dabrafenib treatment for control of the remainder of their disease, particularly in those with isolated progression amenable to SRS.

The heterogeneous nature of disease progression observed in this study, and the availability and success of local therapies to treat isolated areas of progression, demonstrate that RECIST-defined progression does not always mean treatment failure. Unlike chemotherapy, this phenomenon is particularly true for targeted therapies in general, regardless of the type of malignancy they are used to treat, and ceasing treatment at RECIST progression may lead to early cessation of treatment that may still be beneficial to the patient.[16]

In metastatic melanoma, the approach of switching to immunotherapy (eg, ipilimumab) after BRAF inhibitor disease progression has been shown to have little efficacy in retrospective studies,[17, 18] particularly if patients have brain metastases, whereas ongoing treatment with BRAF inhibitors beyond progression may have a survival advantage.[19, 20] No prospective studies have assessed this issue, however, and novel treatments such as PD-1 antibodies may have superior efficacy in this setting.

The management approach to patients with melanoma brain metastases is complicated and changing rapidly. Results of this study suggest that brain metastases respond and progress similarly to EC metastases in patients treated with dabrafenib, and this should assist with choices regarding the nature and timing of local and systemic treatments. Although a prospective clinical trial sequencing local and targeted therapies for patients with brain metastases is required to clarify the general treatment algorithm, a multidisciplinary approach remains critical to ensure optimal outcomes for patients with melanoma brain metastases.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURE
  9. REFERENCES

This work was supported by capital grant funding from the Australian Cancer Research Foundation (recipient: Westmead Institute for Cancer Research). Dr. Long is recipient of a Cancer Institute NSW Research Fellowship. GlaxoSmithKline sponsored the clinical trials from which these data were derived, but had no involvement in the design or conduct of this study.

CONFLICT OF INTEREST DISCLOSURE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURE
  9. REFERENCES

Dr. Menzies has received travel support for conference attendance from GlaxoSmithKline (GSK) and Roche, and honoraria from Roche. Dr. Kefford has received institutional compensation as a consultant advisory board member for GSK, Roche, and Novartis. Dr. Long has received compensation as a consultant advisory board member for GSK, Roche, and Novartis, and has received honoraria from Roche. All other authors made no disclosure.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURE
  9. REFERENCES
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